Acrylonitrile (AN) and methacrylonitrile (MAN) are two structurally related chemicals used in the production of plastics and acrylic fibers. Whereas AN is known to produce tumors in rats, little is known regarding MAN carcinogenicity. The present study compares the ability of the two chemicals to induce cell proliferation in the forestomach (FS; one target of AN carcinogenicity), liver, and glandular stomach. AN was administered to rats daily, for 6 weeks, at 0.43 and 0.22 mmole/kg. MAN was similarly administered at 0.87 and 0.43 mmole/kg. An osmotic minipump containing bromodeoxyuridine (BRDU; 30mg/ml) was implanted subcutaneously 18 hrs before sacrifice. At sacrifice, tissues were removed and processed for H&E and immunohistochemical staining. Histologically, AN caused dose-dependent FS hyperplasia, however, no hyperplastic changes were observed in the FS of MAN-treated rats. In contrast, both chemicals caused a dose-dependent increase in FS mucosal cell proliferation as determined by BRDU incorporation. The fold increase in the unit length labeling index (BRDU labeled cells/mm) over control was 1.8 and 2.3 for the low and high doses of AN, respectively. In MAN-treated rats, the fold increase over control was 1.9 and 2.3 at the low and high doses, respectively. No increase in cell proliferation was detected in the liver or glandular stomach of rats treated with either chemical. These findings were also confirmed by assessing cell proliferation using proliferating cell nuclear antigens (PCNA). The present data indicates that AN induces dose-dependent cell proliferation in a target organ for its carcinogenicity (FS). It also show that MAN induces FS cell proliferation in a dose-dependent manner, however, MAN is less efficacious than AN.